Interpretive Summary: CYP7A1 is a gene that codes for an enzyme that is central to maintaining balance of cholesterol in the body. The activity of the CYP7A1 gene is turned down by fenofibrate, a drug prescribed to lower blood triglyceride levels. Because genetic variation from person to person can affect the response to a drug, it is important to catalog and assess the impact of common genetic variants. Thus, the goal of the study whose findings are reported here was to determine the effect of common genetic variants of the CYP7A1 gene on the degree to which blood levels of cholesterol and triglycerides change when the fenofibrate drug is administered. This was undertaken in a population of American White adults living in Utah and Minnesota who took a standard dose of fenofibrate for three weeks. A common variant in the region controlling CYP7A1 activity was significantly associated with triglyceride and HDL-C (high-density lipoprotein cholesterol) levels, such that persons taking fenofibrate and with two copies of the more common version of the gene displayed a greater reduction in triglycerides and an increase in HDL-C compared to other persons also taking the drug. In contrast, persons harboring two copies of the less common version of a different variant of CYP7A1 showed a greater increase in HDL-C after taking fenofibrate compared to those people with one or zero copies of this less common variant, but with no notable differences in the lowering of triglycerides. In conclusion, our data suggest that common genetic variants in a key cholesterol maintenance gene modulate the triglyceride-lowering and HDL-C-raising effects of fenofibrate and indeed contribute to the inter-individual variation in drug response.

Technical Abstract:
Introduction: CYP7A1 encodes cholesterol 7a-hydroxylase, an enzyme crucial to cholesterol homeostasis. Its transcriptional activity is downregulated by fenofibrate. The goal of this study s to determine the effect of CYP7A1 polymorphisms on lipid changes in response to fenofibrate. Methods: We examined the associations of 3 tagging single nuclear polymorphisms (i6782C>T, m204T>G, 3U12536A>C) at CYP7A1 with triglyceride (TG) and high-density lipoprotein cholesterol (HDL)-C responses to a 3-week treatment with 160 mg/d of fenofibrate in 864 US white participants from the Genetics of Lipid Lowering Drugs and Diet Network study. Results: The m204T>G variant was significantly associated with TG and HDL-C responses with fenofibrate. Individuals homozygous for the common T allele of m204T>G single nuclear polymorphism displayed both the greater reduction of TG (-32% for TT, -28% for GT, -25% for GG, P = 0.004) and an increase of HDL-C response compared with noncarriers (4.1% for TT, 3.4% for GT, 1.2% for GG, P = 0.01). Conversely, individuals homozygous for the minor allele of i6782C>T showed a greater increase in the HDL-C response compared with noncarriers (2.8% CC, 4.5% for CT, 5.8% for TT, P = 0.02), albeit no significant effect on TG response. Conclusions: Our data suggest that common variants at the CYP7A1 locus modulate the TG-lowering and HDL-C-raising effects of fenofibrate, and contribute to the interindividual variation of the drug responses.